1. Field of the Invention
The present invention relates to compounds, pharmaceutical compositions and a method useful for reducing serum cholesterol in humans. More particularly, the invention relates to substituted cyclohexenyl-phosphinyl-hydroxybutyrates and pharmaceutically acceptable salts thereof which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (hereinafter HMG-CoA reductase), pharmaceutical compositions thereof, and a method of inhibiting biosynthesis of cholesterol for the treatment of atherosclerosis, hyperlipidemia and hypercholesterolemia.
2. Related Prior Art
Inhibitors of HMG-CoA are effective in lowering blood plasma cholesterol level as well as inhibiting the biosynthesis of cholesterol in humans. As such, inhibitors of HMG-CoA are useful in the prevention and treatment of coronary heart diseases. The prior art recognizes the importance of such compounds, e.g., Bethridge et al., Brit. Med. J., 4,500 (1975) and Brown et al., Scientific American, 58 Nov. (1984). Illustrative references directed to such compounds follow.
U.S. Pat. No. 4,681,893 to B. D. Roth pertains to trans-6[2-(3-or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones useful as hypochloesterolemic agents.
U.S. Pat. No. 4,668,699 to Hoffman et al. discloses semi-synthetic analogs of compactin and mevinolin and the dihydro and tetrahydro analogs thereof for antihypercholesterolemic application.
U.S. Pat. No. 4,282,155 to Smith et al. is directed to 6(R)-[2-(8'-Etherified-hydroxy-2',6'-dimethylpolyhydronaphtyl1')ethyl]-4(R )-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones for inhibition of biosynthesis of cholesterol.
U.S. Pat. No. 4,567,289 relates to methyl, ethyl, n-propyl, 2-(acetylamino)ethyl, or 1-(2,3-dihydroxy)propyl ester of E-(3R,5S)-7-(4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl)3,5-dihydroxy- 6-heptenoic acid that are HMG-CoA reductase inhibitors.
U.S. Pat. No. 4,611,067 discloses a process for the preparation of HMG-CoA reductase inhibitors which contain a 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one moiety.
Germ. Offen. No. 3,817,375 disclosed HMG-CoA reductase inhibitors having the formula ##STR2## wherein: R is OH, lower alkoxy or lower alkyl;
R.sup.x is H or alkyl; PA0 X is H or --NH; PA0 n is 1 or 2; and PA0 Z is a hydropholic group. PA0 R.sup.x is H or alkyl; PA0 X is --(CH2)a--, --CH.dbd.CH--, --C.tbd.C-- or --CH.sub.2 O; PA0 a is 1, 2 or 3; and PA0 Z is a hydropholic group. PA0 X.sub.1, X.sub.2 and X.sub.3 are independently: PA0 R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently: PA0 n is 0, 1 or 2; PA0 m is 1, 2, 3; and
Germ. Offen. No. 3,817,298 pertains to HMG-CoA reductase inhibitors having the formula ##STR3## wherein: R is OH or lower alkyl;